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Thorax (1959), 14, 146.
THE EFFECTS OF BRONCHODILATORS ON PULMONARY
VENTILATION AND DIFFUSION IN ASTHMA
AND EMPHYSEMA
BY
GERARD LORRIMAN
From Brompton Hospital and the Institute of Diseases of the Chest, London
(RECEIVED
FOR PUBLICATION SEPTEMBER
Impairment of ventilation and of the distribution
of inspired air in asthma and emphysema has
been reported by many authors (Beitzke, 1925;
Kountz and Alexander, 1934; Darling, Cournand,
and Richards, 1944; Baldwin, Cournand, and
Richards, 1949; Bates and Christie, 1950; Beale,
Fowler, and Comroe, 1952), and is the result
mainly, if not entirely, of obstruction of the
airway. Antispasmodics can relieve the obstruction
in asthma, and have also been recommended in
emphysema (Baldwin and others, 1949; Christie,
1952).
Corticotrophin and cortisone - like
substances have been used with benefit in acute
and chronic asthma (Bordley, Carey, Harvey,
Howard, Kattus, Newman, and Winkenwerder,
1949; Friedlaender and Friedlaender, 1951;
Savidge and Brockbank, 1954; Medical Research
Council, 1956), and occasional good results have
been claimed for them in emphysema (Lukas,
1951; Galdston, Weisenfeld, Benjamin, and
Rosenbluth, 1951). Gas exchange in emphysematous lungs is also defective, and this has been
further studied in recent years by the new and
more accurate techniques of measuring the
diffusing capacity for oxygen or carbon monoxide
which have become available (Donald, Renzetti,
Riley, and Cournand, 1952; Filley, MacIntosh,
and Wright, 1954; Bates, Boucot, and Dormer,
1955; Shepard, Cohn, Cohen, Armstrong, Carroll,
Donoso, and Riley, 1955; Bates, Knott, and
Christie, 1956; Ogilvie, Forster, Blakemore, and
Morton, 1957). Shepard and others (1955) and
Bates and others (1956) have shown that, while
both ventilation and diffusing capacity are usually
impaired in emphysema, the impairment may
affect either one or other of these tests of function
disproportionately. As was noted by Donald and
others (1952), reduction of the gas-blood interface
by tissue destruction, and impairment of
distribution of inspired air by airway obstruction,
may both contribute to impairment of the diffusing
22, 1958)
capacity. The proportionate responsibility of
these two factors is, however, unknown. Little has
been published on the diffusing capacity in asthma.
Bates (1952) measured the percentage uptake of
carbon monoxide in 13 young asthmatics aged
12-19 years and found an abnormally low figure
in only one. Ogilvie and others (1957) mention
one asthmatic patient whose diffusing capacity was
normal.
The objects of the present investigation were to
examine the effects of two drugs, isoprenaline
given by inhalation and prednisone orally, on the
ventilation and diffusing capacity in patients with
asthma and emphysema, and to attempt to assess
the degree to which airway obstruction can depress
the diffusing capacity in these disorders. The
bronchodilator action of isoprenaline is well
established (Rossier, 1949; Gilson and HughJones, 1955), and the beneficial action of
prednisone in asthma, and occasionally in
emphysema, has been mentioned above.
SELECTION OF PATIENTS
All the subjects of this investigation suffered
from asthma or emphysema. Most gave a history
of wheezing, but a few were incluided in whom
there was no such history although ventilatory
tests showed evidence of airway obstruction. In
patients classified as asthmatic the dyspnoea and
wheezing were intermittent, though four were
included in whom the breathlessness, previously
intermittent, had become constant in recent
months. In a few infective cases chronic
bronchitis was also present with sputum
containing bacterial pathogens, but in general
bronchitis was not a dominant symptom. At
least one of the following features was also
usually found: a family history of asthma, a
history of other allergic disorders such as
paroxysmal rhinorrhoea, hay fever, or nasal
polypi, and eosinophilia in the blood or sputum.
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EFFECTS OF BRONCHODILATORS ON PULMONARY VENTILATION
The patients classified as emphysematous were all
persistently breathless on exertion, although the
severity of this symptom often varied from time
to time. All but one gave a history of longstanding chronic bronchitis with episodes of
purulent sputum usually containing pathogens.
The exception was a 39-year-old man who
complained of increasing dyspnoea on exertion
since leaving the Army in 1946. He had an
unproductive cough and wheezed only in foggy
weather. Other common findings were radiological
evidence of emphysema (hyperinflation of the
lungs, low flat diaphragm, large main pulmonary
arteries with poor peripheral vessels, bullae),
chronic central cyanosis, and pulmonary P waves
in the electrocardiogram. The asthmatics were on
the whole younger (range 17-55 years) than the
emphysematous group (range 39-78 years). It
was impossible to decide whether " asthma " or
" emphysema " was the appropriate group for
some patients.
GRADING OF WHEEZING. -Wheezing may be
caused by true bronchospasm, perhaps associated
with mucosal oedema, or by airway obstruction
from other causes, such as bronchial damage from
chronic infection, collapse of bronchial walls
during expiration due to loss of elasticity of the
lung, or, as is seen in fatal cases of status
asthmaticus, from blocking of the small peripheral
bronchi by plugs of inspissated mucus. It was
graded as follows:
Severe.-Breathing laboured at rest, expiratory
wheeze, generalized rhonchi.
Moderate.-Breathing not laboured at rest,
expiratory wheeze, generalized rhonchi.
Slight.-Prolonged expiration, scattered rhonchi.
It is to be noted that airway obstruction severe
enough to cause dyspnoea at rest may be present
without any wheeze, the only auscultatory sign
sometimes being weak breath sounds. Patients
in status asthmaticus were excluded from the
investigation because they were too ill to carry
out the tests.
METHODS
The ventilatory test selected was the forced
expiratory volume at one second (Gaensler, 1951),
because it gives information equivalent to that
provided by the maximal ventilatory volume and is
less exhausting for the patient. Now generally known
as the FEV,, it was measured on the spirogram
obtained from a spirometer of the type described by
Bernstein, D'Silva, and Mendel (1952) at a peripheral
drum speed of 16 mm. per second (Gandevia, Hume,
and Prime, 1957). The mean was taken of three
satisfactory tracings.
147
The diffusing capacity for carbon monoxide (DL)
was estimated by the steady-state technique of Bates
and others (1955) on a simplified circuit devised by
Prime (MacNamara, Prime, and Sinclair, 1959). This
method is based on the assumption that the CO
tension of the end-tidal sample is equivalent to the
mean alveolar CO tension. The DL is then calculated
by dividing this figure into the rate of uptake of CO
and is expressed as ml./min./mm. Hg. However,
in normal subjects, as Bates points out, the end-tidal
CO tension is likely to be lower than the mean
alveolar CO tension, and the value for DL will be
correspondingly high. In patients with an uneven
distribution of inspired air, such as is found in
asthma and emphysema, the end-tidal CO tension
may be higher or lower than the mean alveolar
CO tension, and the magnitude of the error thus
introduced cannot be known. Duplicate estimations
of DL showed surprisingly good agreement in the
present series even in the presence of moderately
severe airway obstruction, suggesting that the error
due to uneven distribution does not vary greatly over
short periods. Although the method of Filley and
others (1954) probably reduces this error, it has the
disadvantage of requiring arterial puncture, and this
severely limits its applicability in the field of clinical
research. Bates's technique, on the other hand, does
not require arterial puncture, is simply and quickly
performed, and can be repeated frequently at short
intervals so that duplicate estimations can be made.
Before the isoprenaline test the DL was estimated
with the patient sitting, duplicate estimations being
made in most cases and the mean value taken. The
FEV, was recorded and the patient then inhaled an
aerosol of 1% isoprenaline solution given through
a Bright inhaler for one and a half minutes at a flow
rate of eight litres per minute. The amount of solution
inhaled during this time was approximately 0.75 ml.
In most cases tachycardia and palpitation developed,
breathing was often subjectively easier, and rhonchi
fewer. After eight minutes the DL and FEV,
estimations were repeated.
The dosage of prednisone is described later.
RESULTS
ISOPRENALINE. - Forty - seven patients were
investigated, 38 men and nine women. There were
no essential differences in the results as between
the sexes. Twelve patients, eight men and four
women, were certainly asthmatics. All the
remainder are classified below as cases of chronic
bronchitis and emphysema, although in six (two
men and four women) there was doubt as to the
group in which they should be placed. At the
time of testing wheezing was moderately severe
in four, moderate in 14, slight in 14, and absent in
15 patients. Among the last group wheezing had
been present in the recent past in 10 and had not
been observed at any time in five. The effects on
FEV1 and D, will be described separately.
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148
GERARD LORRIMAN
TABLE I
EFFECT OF ISOPRENALINE AEROSOL ON FEV1 AND DL IN 47 PATIENTS WITH ASTHMA OR CHRONIC
BRONCHITIS AND EMPHYSEMA
Group
Diagnosis
..
Asthma ..
Chronic bronchitis
and emphysema
Asthma ..
Chronic bronchitis
L and emphysema
No.
Cases
9
12
3
23
23
Mean Age
(Range) in Years
40 9
FEV before
Mean
Isoprengalie
(Range
in ml.)
1,140
(26-55)
(650-2,245)
(39-70)
(340-1,855)
1,560
(415-3,435)
1,030
(385-2,555)
54-2
29-3
(17-47)
53-5
(43-63)
765
Mean Increase
in FEV after
Isoprenafite
(Range
in ml.)
500
(260-860)
290
(130-695)
230
(70-630)
80
(-50to +220)
Mean DL before
Isoprenaline
(Range in Hg)
ml.,min./mm.
11-7
(6-8-18-7)
9-2
(3-3-17-3)
17
(7-7-28)
10-2
(29-177)
Mean DL after
Isoprenaline
(Range in Hg)
ml./min./mm.
12-3
(6-6-22-7)
8-4
(2-9-17-9)
13-6
(6-8-17-5)
9-8
(3*0-152)
Group I-Every patient had an increase of 25% or more in FEV1 after isoprenaline.
,, II- ,, ,, ,, ,, ,, ,, lessthan25%inFEVV1,
.
.
A. Effect on FEV1.-The results shown in a girl aged 24 years with long-standing infective
Table I are divided into two groups according to asthma, who, in spite of marked airway obstruction
the magnitude of the response to isoprenaline, an (FEV1 415 ml.) which responded poorly to
increase of 25% being taken as the arbitrary isoprenaline, had a normal DL of 15 ml./min./
dividing line. The mean increase in FEV1 was mm. Hg. With the exception of one asthmatic
greater in the asthmatic patients in each group, boy aged 17 years who was free from bronchothough there was a very wide scatter around the spasm on the day of the test and responded with
means. The most important point shown in an increase in FEV1 of less than 25%, all the
Table I is the absence of any significant increase patients with no wheezing, i.e., the " nil " group in
in mean DL even when there was a significant Table III, were suffering from chronic bronchitis
and varying degrees of emphysema. In only one
improvement in FEV1 after isoprenaline.
Table II shows that younger patients responded was the increase in FEVI impressive in absolute
better than- older, the reason being that eight of terms, a man aged 38 years who had been
the nine patients under the age of 41 were breathless on exertion for 11 years and wheezed
only in foggy weather. His FEV1 increased from
asthmatics.
965 ml. to 1,360 ml. and he was thus the only
TABLE II
RESPONSE TO ISOPRENALINE IN RELATION TO AGE patient in the series who had no auscultatory
signs of bronchospasm and showed a large increase
in FEV1 after isoprenaline.
% Increase in FEV1 after Isoprenaline
Age Group
(Years)
> 25%
< 25%
The results confirm the bronchodilator action
of isoprenaline. Its comparative failure in the
17-40
7
2
41-70
14
24
severe group suggests that part of the airway
obstruction was due to some mechanism other
The response in relation to the severity of than bronchospasm, or that isoprenaline as given
in this investigation was not powerful enough to
wheezing is shown in Table III.
release severe bronchospasm.
TABLE III
B. Effect on DL.-That there is a relationship
RESPONSE TO ISOPRENALINE IN RELATION TO DEGREE
between FEV1 and DL is shown in Fig. 1, where
OF WHEEZING
the values for log FEV1 and for DL before
% Increase in FEVV1 after
treatment are plotted for each of 63 patients with
Degree
Isoprenaline
Total
of Wheezing
asthma or chronic bronchitis and emphysema. It
>25%
<25%
will be seen that when the FEV1 is low the DL
1
Severe ..
3
4
is likely also to be low. In view of this it might
Moderate
8
6
14
..
..
Slight
8
6
14
be expected that an increase in DL would occur
Nil
..
4
11
15
after isoprenaline in those patients whose FEV1
improves considerably, but there is no indication
The best results were obtained in those patients of this in Table I. With such a wide scatter
with slight or moderate wheezing, and these around the means, however, a real correlation
two groups included 10 of the 12 asthmatics. might be concealed. Therefore, in Fig. 2 are
In the severe group there was one asthmatic, plotted the percentage changes in FEV1 and in
o
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149
EFFECTS OF BRONCHODILATORS ON PULMONARY VENTILATION
400"
0
00
0
20001
0
0
1000
600
a
-
00
o0f
uJ
U-
o,o
-
+130
0
,zC°D°o°
-
400
0
0
0
0
9
0
0
c
for the percentage change in minute volume
after isoprenaline varied from - 47 % to + 102%,
with a mean of + 10.4%. It therefore seems that
changes in resting DL after isoprenaline are
associated with unpredictable changes in minute
volume and are unrelated to changes in FEV1.
It will be observed that the regression line of
Fig. 3 cuts the abscissa very slightly to the left of
the origin, and that the points for 10 of the 12
0
CD
ti 1o
0I0
0
200[
w
I
Iof%^
I
I5
10
5
I
+90
00
C
I
U
25
20
30
_
0
C
a
0
bE
60
0
u
4
x-
o
0
0
'9
0
c
@
900f
20
L
0
0~
0
O1
89°
p
_50
V0
o
0
+S
+330
°0
0
00
0
0
bu
0
0
to
FIG. 1.-Relationship between DL and FEV1 in 63 cases of asthma
or chronic bronchitis and emphysema before treatment.
LU
0
0
DL (ml./min./mm. Hg)
lOOr
0
c
._
O09
0
00
all
0
.
*
0
0
0
D _
30oO /
30e */o
*
-50
0
0
0
0
0
1
4
-
r
-0 76
-loo +10
+30
0.14
1-
+50
+ 70
Percentage Change in DL
0
V
*
-30
0.6S X MV.-7 5
S.E
° 0
so
Percentage Change in DL
FIG. 2.-Relationship between percentage changes in DL and FEV1
after isoprenaline. Open circles=patients with chronic bronchitis and emphysema. Black circles= asthmatics.
DL after isoprenaline for all 47 patients. It is
clear that there is no correlation, and this is
equally true of asthmatics and of patients suffering
from chronic bronchitis and emphysema.
Because MacNamara, Prime, and Sinclair (1959)
have shown a direct relationship between minute
volume and DL at rest, the percentage changes in
these values after isoprenaline for all 47 patients
were plotted in Fig. 3, from which it is evident
that there is a highly significant degree of
correlation. There is no evidence that isoprenaline,
under the conditions of the present investigation,
has any consistent action on the minute volume,
FIG. 3.-Relationship between percentage changes in DL and minute
volume after isoprenaline. Open circles= patients with chronic
bronchitis and emphysema. Black circles=asthmatics.
asthmatics lie to the right of the regression line.
Therefore, if the asthmatics were excluded, the
regression line would shift further to the left and
would cut the abscissa still more on the negative
side of the origin. This suggests the possibility
that in emphysema, if the minute volume were
kept unchanged, isoprenaline by aerosol might
actually cause a slight fall in mean resting DL
over a sufficient number of patients.
PREDNISONE. Prednisone was given to 13
patients and corticotrophin to one, in whom
routine antispasmodics had failed to give adequate
relief. All had a history of wheezing at some time.
Cases 1-5, 10, 13, and probably 14 (see Table IV
and below) were asthmatics, and the remainder
were suffering from chronic bronchitis and severe
emphysema. When steroid treatment was begun
wheezing was moderate in Cases 2, 3, 13,
and 14, absent in Cases 11 and 12, both of
which were, however, very breathless on exertion,
and in the remainder was severe. Before
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150
GERARD LORRIMAN
TABLE IV
EFFECT OF PREDNISONE ON FEV1 AND DL IN 12 PATIENTS
SUFFERING FROM ASTHMA OR CHRONIC BRONCHITIS
AND EMPHYSEMA
FEV1
Case Sex Age
berfore
Diagnosis
nisone
FEVy
on
I
F
33
Asthma
..
-
1,550
M
29
,,
..
1,830
3,760
3
M
47
..
850
1,390
4
F
26
,,
..
1,250
1,640
S
M
47
,,
..
835
2,260
6
M
55
775
850
7
M
54
,,
,,
585
525
8
M
46
,,
,,
1,030
660
9
M
43
,,
,,
900
1,600
10l
F
24
Infectiveasthma
415
620
11
M
50
1,035
935
12
M
78
Chronic bronchitis and
emphysema
1,000
785
,,
,,
DL
8-3
(8-1)
16-7
(7-9)
10-2
(12-7)
7-7
(7 0)
7-7
(12-2)
7-8
(8-1)
15-5
(9*3)
30-1
(8 4)
16-9
(11-4)
18-6
(6 6)
18-8
(14-4)
11-8
(81)
on
PredPred- nisone nisone
nisone (Minute
(Minute
(ml.) Volume) Volume)
2
Chronic bronchitis and
emphysema
DL
before
Pred-
8
(11-9)
9.9
(6)
9.5
(8-9) !
15-3
(7*7)
13-1
(10-3)
11
(11-2)
5.9
(8 4)
10-5
(9-3)
9.9
(9 6)
I 16-2
I (8-8)
174
(85)
9-2
(11-0)
DL is expressed in ml./min./mm. Hg. Minute volume (in brackets
below each corresponding DL) in litres. For description of cases and
dosage of prednisone, see text.
prednisone or corticotrophin was given care was
taken to exclude contraindications, especially
evidence of coronary disease, a history suggestive
of peptic ulceration, or a family history of diabetes
mellitus. The initial daily dose of prednisone
varied from 30 mg. to 100 mg. Doses above
50 mg. were given for one day only and then
usually rapidly reduced by 10 mg. a day to 20 mg.
daily or less. Tests were carried out before and
at intervals ranging from 36 hours to six weeks
after beginning treatment.
The results for Cases 1-12 are shown in Table
IV, while Cases 13 and 14 are described briefly
below. The patients fall into two groups. In
Cases 1-5 there was marked clinical and objective
improvement, whereas in Cases 6-12 there was
little response; although the DL in Cases 6 and
11 and the FEVI in Case 9 increased appreciably,
there was little clinical improvement. Even
excluding the 78-year-old patient, the average age
was lower for the group responding well (36.2
years as against 45.3), and the mean duration of
symptoms shorter (9.1 years compared with 27.3).
Case 10, the only asthmatic who did not respond
to prednisone, was the girl with infective asthma
mentioned previously. Her wheezing was hardly
improved by 50 mg. dailv of prednisone for two
weeks.
Case 13 was a 38-year-old man who had suffered
from asthma since the age of 7 years. He was
admitted to hospital during a relapse, and, because
moderate wheezing persisted after treatment with
routine antispasmodics, he was given a short
course of corticotrophin (40 units of the gel twice
daily, rapidly reduced), on which treatment
wheezing was almost abolished. His results were
as follows:
Minute
Volume
Before treatment
On routine antispasmodics
On corticotrophin
DL.
(litres)
(ml./min./
mm. Hg)
14-3
15-6
14-7
11.9
16-3
18-4
FE(l
(m.
1,000
1,350
1,615
In this case therefore corticotrophin added
somewhat to the substantial measure of
improvement already achieved by routine
antispasmodics.
Case 14 was a 55-year-old man who only
nine months previously had suddenly developed
persistent shortness of breath, followed many weeks
later by wheezing. After seven days' treatment
with 20 mg. prednisone daily, moderate wheezing
persisted. The dose of prednisone was therefore
increased to 80 mg. for one day and reduced by
10 mg. daily thereafter. Wheezing was almost
immediately abolished, and on the seventh day, at
a dose again of 20 mg., the DL and FEVI
estimations were repeated. The results were as
follows:
On 20 mg. prednisone
..
daily for 7 days
After 80, 70, 60, 50, 40,
30, 20 mg. on succes..
..
sive days
Minute
Volume
(litres)
(ml./Minl./
DL
FEV1
mm. Hg)
(MI.)
167
18 7
2,215
12-4
24.8
3,025
(ml.)
This patient was subsequently discharged, still
free from bronchospasm, on a maintenance dose
of 10 mg. prednisone daily.
In all, therefore, seven patients responded well
to prednisone or corticotrophin. Of these, four
had previously been tested with isoprenaline, an
increase of more than 25% in FEVI occurring in
three. Among the seven patients who responded
poorly to prednisone, five had been tested with
isoprenaline, an increase of more than 25 % in
FEV1 occurring in only one.
Three features differentiate the increase in DL
among patients responding well to prednisone
from any increase in DL following isoprenaline.
With prednisone the increase was much greater;
it was associated with a considerable increase in
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EFFECTS OF BRONCHODILATORS ON PULMONARY VENTILATION
and there was a striking absence of any
proportionate increase in minute volume.
FEVI,
DISCUSSION
In interpreting the significance of changes in DL,
a distinction must be drawn between those cases
in which an increase in DL is accompanied by a
proportionate increase in minute volume, and
those in which the minute volume remains
substantially unchanged or even falls. The
former association, first noted by MacNamara,
Prime, and Sinclair (1959), is found to occur
regularly with the present technique of estimating
DL. The reason for this increase is not altogether
clear, but presumably, as in exercise, hyperventilation is bringing into use the respiratory reserve.
When, however, for the same minute volume a much
greater quantity of gas is transferred from the
inspired air into the blood, a real improvement in
lung function is clearly implied. Such is the case
in those patients whose DL improves on
prednisone.
The reason for the failure of isoprenaline to
increase the DL when it produces an increase in
FEVI is not clear. There seems to be no obvious
explanation in the pharmacology of isoprenaline,
which is said to cause brief vasodilatation and
more prolonged tachycardia with an increase in
the cardiac output (Dautrebande, 1952; Sollmann,
1957). If the cardiac output rises it is difficult to
envisage any general pulmonary vasoconstriction
which might reduce the gas-blood interface and
thus decrease the uptake of CO. In emphysematous patients the improved FEV, after
isoprenaline may represent the ventilation of
additional alveoli which are not well perfused with
blood. In asthmatics, however, it seems more
probable that any freshly ventilated alveoli would
be well perfused, and yet the failure of DL to
increase after isoprenaline is just as pronounced
in asthma as in emphysema. Alternatively it
is possible that the bronchodilator action of
isoprenaline does not extend as deeply as the
smallest bronchioles, any increase in FEV,
representing a greater volume of bronchial and
bronchiolar, but not of additional alveolar, space.
If so, the magnitude of the increase-up to 860 ml.
-is surprising. Again, there may be a fallacy in
assuming that an increase in FEV1, which, as its
name implies, is a measure of forced expiration,
is necessarily reflected in improved ventilation at
rest. However, it may be noted that in Cases 3
and 4 considerable increases in DL on prednisone
were associated with but moderate increases in
FEVp, 540 ml. and 390 ml. respectively.
151
The results with prednisone and corticotrophin
were clear cut. All the asthmatics except one
responded very well, while all patients with chronic
bronchitis and emphysema, and the girl with long-
standing infective asthma, responded poorly.
There seems little doubt that prednisone and
corticotrophin act by abolishing bronchospasm
and perhaps mucosal oedema or hypersecretion,
but the mechanism by which these effects are
brought about is not clear. The work of Citron
and Scadding (1957) has greatly clarified the
problem of the variable action of cortisone
on the delayed, tuberculin type of sensitivity
reported by previous authors (Long and Favour,
1950 ; Carey, Harvey, Howard, and Winkenwerder,
1950). Reports regarding its effect on the
immediate, histamine type of sensitivity reaction,
however, remain conflicting. Goth, Allman,
Merritt, and Holman (1951) found that injecting
dogs with the surface-active agent Tween 20
caused a liberation of histamine from the tissues
and a consequent fall in blood pressure, and this
effect was repeated with further injections of the
same substance. Cortisone did not prevent the
fall in blood pressure after the first dose of Tween
20, but did prevent a fall after a second dose.
The authors interpreted these findings as evidence
that cortisone is unable to counteract the effects
of histamine already formed in the tissues, but
that it prevents the synthesis of further histamine.
Schayer, Davis, and Smiley (1955) found that
rat skin, when incubated with 14C L-histidine,
converted a small percentage to 14C histamine
which remained in a bound condition in the skin.
Pre-treatment of the rats with cortisone impaired
this conversion. Lovell, Goodman, Hudson,
Armitage, and Pickering (1953), in a series of
experiments in man, confirmed the suppressive
action of cortisone on the delayed type of
sensitivity reaction, but concluded that it had little
or no effect on the immediate skin reaction to
histamine. Holti (1956) has criticized the work of
Lovell and others, on the grounds that they
measured weals only up to 10 minutes after
pricks with histamine solution, and that they
did not compare prick tests at identical skin
temperatures. Holti made careful measurements
of weals 10 and 20 minutes after pricking
histamine solutions into the skin, with strict
control of skin temperature, and showed that oral
cortisone. while its effect after 10 minutes was
slight, exerted a clear-cut suppressive action at
20 minutes. This effect was more evident with
large doses of cortisone. These findings may have
some bearing on the mode of action of cortico-
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152
GERARD LORRIMAN
steroids in asthma, though it must be admitted
that antihistamines have little effect in asthma.
While in the present series the history was
of value in forecasting the likely response to
prednisone, the auscultatory signs differed little in
character or severity as between successes and
failures. A good response to prednisone seemed
more likely in patients whose FEV1 increased by
over 25% after isoprenaline.
The action of prednisone on the DL in asthmatics
is evidence that airway obstruction can depress
the diffusing capacity. By analogy, in cases of
emphysema, although reduction of the capillary
bed by tissue destruction is no doubt one important
factor in impairment of the DL, it seems probable
that airway obstruction also plays a significant
part. It is of interest that as long ago as 1925
Beitzke, on the basis of histological examination
of normal and emphysematous lungs, together
with experiments on the mixing of plain and
coloured water by to-and-fro piston action in
glass tubes of different shapes, suggested that the
impairment of gas exchange in emphysema was
due less to reduction of the alveolar surface area
than to poor mixing of inspired and alevolar air.
Two final points may be noted in connexion
with the response to prednisone. In Cases 6 and
11, although there was little clinical improvement
and the FEV1 remained substantially unchanged,
the DL increased significantly, suggesting that
improved ventilation may not be the whole
explanation of the action of prednisone. The
results in Case 14 show that when moderate doses
of prednisone fail to abolish bronchospasm, a short
course with a heavy dosage may succeed, and the
spasm may thereafter be controlled by a small
maintenance dose.
CONCLUSIONS
In 47 patients with asthma or emphysema,
isoprenaline, even when it caused a considerable
increase in the forced expiratory volume at one
second (FEV1), did not increase the diffusing
capacity for carbon monoxide (DL), changes in
which were associated with unpredictable changes
in minute volume.
Prednisone or corticotrophin caused clinical
and objective improvement in six asthmatics, but
had little effect on one case of long-standing
infective asthma and on seven cases of chronic
bronchitis and emphysema. In patients responding
well, a pronounced increase in DL occurred,
associated with a considerable increase in FEV1
and without any proportionate change in minute
volume.
Bronchospasm can markedly depress the DL
A normal DL may, however, be found in
association with moderately severe bronchospasm.
In assessing the significance of changes in DL at
rest, the minute volume must be taken into
account ; a proportionate change in minute volume
considerably reduces the significance of any
alteration in DL.
I wish to thank Dr. Clifford Hoyle and Dr. F. J.
Prime for their constant encouragement, advice, and
criticism throughout this investigation, which was
carried out with the aid of a grant from the Research
Committee of the Hospitals for Diseases of the Chest.
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The Effects of Bronchodilators
on Pulmonary Ventilation and
Diffusion in Asthma and
Emphysema
Gerard Lorriman
Thorax 1959 14: 146-152
doi: 10.1136/thx.14.2.146
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